DE2541855A1 - 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II - Google Patents
4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE IIInfo
- Publication number
- DE2541855A1 DE2541855A1 DE19752541855 DE2541855A DE2541855A1 DE 2541855 A1 DE2541855 A1 DE 2541855A1 DE 19752541855 DE19752541855 DE 19752541855 DE 2541855 A DE2541855 A DE 2541855A DE 2541855 A1 DE2541855 A1 DE 2541855A1
- Authority
- DE
- Germany
- Prior art keywords
- pyrrolidone
- groups
- general formula
- dimethoxyphenyl
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000005518 carboxamido group Chemical group 0.000 claims description 5
- 230000008030 elimination Effects 0.000 claims description 5
- 238000003379 elimination reaction Methods 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- KJEYEDTXTAUVBL-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-2-oxopyrrolidine-1-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)N(C(N)=O)C1 KJEYEDTXTAUVBL-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- WDVSHHCDHLJJJR-UHFFFAOYSA-N Proflavine Chemical compound C1=CC(N)=CC2=NC3=CC(N)=CC=C3C=C21 WDVSHHCDHLJJJR-UHFFFAOYSA-N 0.000 claims 2
- ZGWMMFTXTXJLIH-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-2-oxo-n-phenylpyrrolidine-1-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)N(C(=O)NC=2C=CC=CC=2)C1 ZGWMMFTXTXJLIH-UHFFFAOYSA-N 0.000 claims 1
- 239000012445 acidic reagent Substances 0.000 claims 1
- 125000005907 alkyl ester group Chemical group 0.000 claims 1
- 210000003056 antler Anatomy 0.000 claims 1
- 235000015244 frankfurter Nutrition 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- -1 • '-arboxy groups Chemical group 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 3
- 229960001076 chlorpromazine Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- KXTAOXNYQGASTA-UHFFFAOYSA-N 2-benzylidenepropanedioic acid Chemical compound OC(=O)C(C(O)=O)=CC1=CC=CC=C1 KXTAOXNYQGASTA-UHFFFAOYSA-N 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- VUWPIBNKJSEYIN-UHFFFAOYSA-N diethyl 2-benzylidenepropanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CC1=CC=CC=C1 VUWPIBNKJSEYIN-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 1
- JMVIVASFFKKFQK-UHFFFAOYSA-N 1-phenylpyrrolidin-2-one Chemical class O=C1CCCN1C1=CC=CC=C1 JMVIVASFFKKFQK-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- QQNCKWXXHNJAQX-UHFFFAOYSA-N 2-[(4-hydroxy-3-methoxyphenyl)methylidene]propanedioic acid Chemical compound COC1=CC(C=C(C(O)=O)C(O)=O)=CC=C1O QQNCKWXXHNJAQX-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000006228 2-isobutoxyethyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 description 1
- BXYQHDXDCJQOFD-UHFFFAOYSA-N 3-cyanopropanoic acid Chemical class OC(=O)CCC#N BXYQHDXDCJQOFD-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- JNRKFSJWVCILHE-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)pyrrolidin-2-one Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)NC1 JNRKFSJWVCILHE-UHFFFAOYSA-N 0.000 description 1
- OVRPDYOZYMCTAK-UHFFFAOYSA-N 4-(4-chlorophenyl)pyrrolidin-2-one Chemical compound C1=CC(Cl)=CC=C1C1CC(=O)NC1 OVRPDYOZYMCTAK-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229940095564 anhydrous calcium sulfate Drugs 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- RKGDXSLYBJAUHD-UHFFFAOYSA-N diethyl 2-[(3-hydroxy-4-methoxyphenyl)methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CC1=CC=C(OC)C(O)=C1 RKGDXSLYBJAUHD-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- MIHRVXYXORIINI-UHFFFAOYSA-N ethyl 2-cyanopropionate Chemical compound CCOC(=O)C(C)C#N MIHRVXYXORIINI-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- IOMFXMPKQPMLND-UHFFFAOYSA-N n-benzyl-4-(3,4-dimethoxyphenyl)-n-methyl-2-oxopyrrolidine-1-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1CC(=O)N(C(=O)N(C)CC=2C=CC=CC=2)C1 IOMFXMPKQPMLND-UHFFFAOYSA-N 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001021 polysulfide Polymers 0.000 description 1
- 239000005077 polysulfide Substances 0.000 description 1
- 150000008117 polysulfides Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000004622 sleep time Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
4·- (Polyalkoxy-phenyl)-2-pyrrolidone II (Zusatz zu P 24 13 935-3)4- (Polyalkoxyphenyl) -2-pyrrolidone II (addition to P 24 13 935-3)
Im Hauptpatent (Patentanmeldung P 24 13 935·3) werden racemische und optisch aktive 4-(Polyalkoxy-phenyl)-2-pyrrolidone der allgemeinen Formel IIn the main patent (patent application P 24 13 935 · 3) racemic and optically active 4- (polyalkoxyphenyl) -2-pyrrolidones of the general formula I.
(D(D
R1 und R0 gleich oder verschieden sind und Kohlenwasserstoffgruppen mit bis zu 18 C-Atomen oder Alkylgruppen mit 1-5 C-Atomen, die durch ein oder mehrere Halogenatcme, Hydroxygruppen, •'-arboxygruppen, Alkoxygruppen, Alkoxycarbonyl - , Carboxamido- oder gegal<en.enfalls substituierte Aminogruppen substituiert sind, oderR 1 and R 0 are identical or different and are hydrocarbon groups with up to 18 carbon atoms or alkyl groups with 1-5 carbon atoms, which are replaced by one or more halogenates, hydroxyl groups, • '-arboxy groups, alkoxy groups, alkoxycarbonyl, carboxamido or optionally substituted amino groups are substituted, or
709813/0970709813/0970
ORfQlNAL INSPECTEDORfQlNAL INSPECTED
it—t it* '4\Za ί it —t it * '4 \ Za ί
— ^ — GewerhSidacr R - ^ - GewerhSidacr R
R und R„ gemeinsam eine Alkylengruppe mit 1 bis 3 C-Ätomen,R and R "together represent an alkylene group with 1 to 3 carbon atoms,
JL ti* " JL ti * "
R- ein Wasserstoff atom oder eine JMethoxygruppe,R- a hydrogen atom or a methoxy group,
R. ein Wasserstoffatom, eine Alkyl-, Aryl- oder AcylgruppeTypically a hydrogen atom, an alkyl, aryl or acyl group
X ein Sauerstoff- oder Schwefelatom bedeuten, und Verfahren zu ihrer Herstellung beschrieben.X denote an oxygen or sulfur atom, and processes for their preparation are described.
In weiterer Ausbildung dieser Erfindung wurde nun gefunden, daß k- (Polyalkoxy-phenyl )-2--pyrrolidone mit R, in der Bedeutung von -CO-R-, wobei R_ für 0-Alkyl, O-Aryl, O-Aralkyl, NH-,NH-Alkyl, NH-Aryl, NH-Aralkyl, NAlkyl , NAryl., undIn a further development of this invention it has now been found that k- (polyalkoxyphenyl) -2 - pyrrolidones with R, meaning -CO-R-, where R_ is 0-alkyl, O-aryl, O-aralkyl, NH-, NH-alkyl, NH-aryl, NH-aralkyl, NAlkyl, NAryl., And
vArvi
N\Ä1f. ^ steht, bei gleichem pharmakologischen Wirktsngsspektrum
eine ausgeprägt protrahierte Wirkung zeigen.vArvi
N \ Ä1 f. ^ Stands, show a pronounced protracted effect with the same pharmacological spectrum of effects.
Die vorliegende Erfindung betrifft somj.t eine weitere Aitsbildung der Erfindung gemäß Hauptpptent (Patentanmeldung P 2k 13 935·3) von neuen racemischen und optisch aktiven k- (Polyalkoxy-phenyl)-2-pyrrolidonen der allgemeinen Formel IThe present invention thus relates to a further development of the invention according to the main patent (patent application P 2k 13 935.3) of new racemic and optically active k- (polyalkoxyphenyl) -2-pyrrolidones of the general formula I.
~ 3 — 709813/0970~ 3 - 709813/0970
ν1 ;eB6ν1; eB6
ν.·»νι ti__i cti vV.« t \' Gewerblicher Rechtsschutz: ν. · »νι ti__i cti vV.« t \ ' Intellectual property rights:
R1 und H_ gleich oder verschieden sind und Kohlenwasserstoffgruppen
mit bis zu 18 C-Atomen oder Alkylgruppen mit 1-5 C-Atomen, die durch ein oder mehrere Halogenatome, Hydroxygruppen,
Carboxygruppen, Alkoxygruppen, Alkoxycarbonyl-,
Carboxamido- oder gegebenenfalls substituiei-te Aminogruppen
substituiert sind,
oderR 1 and H_ are identical or different and are hydrocarbon groups with up to 18 carbon atoms or alkyl groups with 1-5 carbon atoms which are substituted by one or more halogen atoms, hydroxyl groups, carboxy groups, alkoxy groups, alkoxycarbonyl, carboxamido or optionally substituted Amino groups are substituted,
or
R1 und R0 gemeinsam eine Alkylengruppe mit 1 bis 3 C-Atomen,
R ein Wasserstoffatom oder eine Methoxygruppe,
R. die Gruppierung CO-R , wobei R für 0-Alkyl, O-Aryl, 0-Aralkyl,
NHn-, NH-Alkyl, NH-Aryl, NH-Aralkyl, NAlkyl.,
NAryl2 und N<^^ steht,
X ein Sauerstoff- oder Schwefelatom
bedeuten, und Verfahren zu ihrer Herstellung.R 1 and R 0 together are an alkylene group with 1 to 3 carbon atoms, R is a hydrogen atom or a methoxy group, R. is the grouping CO-R, where R is 0-alkyl, O-aryl, 0-aralkyl, NH n -, NH-alkyl, NH-aryl, NH-aralkyl, NAlkyl., NAryl 2 and N <^^,
X is an oxygen or sulfur atom
mean and process for their preparation.
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- >r · . SCHLHlNG AG- > r ·. SCHLHlNG AG
Gewerbl.Re cht aschuGewerbl.Re cht a scatterbrained
Die Verbindungen der allgemeinen Formel "ΐ "besitzen ein asymmetrisches Kohlenstoffatom und können daher sowohl als Racemate als auch als optische Antipoden vorliegen.The compounds of the general formula "ΐ" have a asymmetric carbon atom and can therefore exist both as racemates and as optical antipodes.
Als Kohlenwasserstoffgruppen E, und E^ kommen gesättigte und ungesättigte, geradkettige und verzweigte Alkylgruppen mit 1 "bis 18 Kohlenstoffatomen in Betracht, ferner Cycloalkyl- und Cycloalkyl-alkylgruppen mit vorzugsweise 3 bis 7 Kohlenstoffatomen sowie Aryl- und Aralkylgruppen mit vorzugsweise 6 bis 10 Kohlenstoffatomen.The hydrocarbon groups E and E ^ are saturated and unsaturated, straight-chain and branched alkyl groups with 1 "to 18 carbon atoms, also cycloalkyl and cycloalkyl-alkyl groups with preferably 3 to 7 Carbon atoms and aryl and aralkyl groups with preferably 6 to 10 carbon atoms.
Geeignete Alkylgruppen sind zum Beispiel. Methyl, Äthyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, 2-Methylbutyl, 2,2 -Dimethylpropyl, Hexyl, Heptyl, Octyl, Konyl, 1,2-Dimethylheptyl, Decyl, Undecyl, Dodecyl und Stearyl. Die Alkylgruppen können auch ungesättigt sein und zum Beispiel Vinyl, 1-Propenyl, 2-Propenyl, 2-Propinyl, 3-Methyl-2-propenyl usw. bedeuten. . Alkylgruppen mit·vorzugsweise 1 bis 5 C-Atomen können auch ein- oder mehrfach substituiert-sein, beispielsweise durch Halogen, insbesondere Fluor, Chlor und Brom. Beispiele für halogensubstituierte Alkylgruppen sind: 2-Chloräthyl, 3-Chlorpropyl, 4-Brpmbutyl., Difluormethyl, Trifluormethyl, 1,1,2-Trifluor-2-chloräthyl, 3,3,3-TrCfluorpropyl, 2,2,3,3,3-Pentafluorpropyl, l,l,l,3,3,3THexafluor-2-propyl. Als Sxibstituenten der Alkylgruppen kommen ferner inf rage: Hydroxygruppen, zum BeispielSuitable alkyl groups are, for example. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, heptyl, octyl, konyl, 1,2-dimethylheptyl, decyl, undecyl, dodecyl and stearyl . The alkyl groups can also be unsaturated and can mean, for example, vinyl, 1-propenyl, 2-propenyl, 2-propynyl, 3-methyl-2-propenyl, etc. . Alkyl groups with preferably 1 to 5 carbon atoms can also be substituted one or more times, for example by halogen, in particular fluorine, chlorine and bromine. Examples of halogen-substituted alkyl groups are: 2-chloroethyl, 3-chloropropyl, 4-bromobutyl., Difluoromethyl, trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl, 3,3,3-Tr C fluoropropyl, 2,2,3 , 3,3-pentafluoropropyl, 1,1,1,3 T hexafluoro-2-propyl. The following can also be used as Sxibstituenten the alkyl groups: Hydroxy groups, for example
.- 5 709813/0970 .- 5 709813/0970
^ - /5 - · Gewerbl.Rechtsschui^ - / 5 - Commercial law school
als 2-Hydroxyäthyl oder 3-Hydroxypropyl,. Carboxygruppen zum Beispiel als Carboxymethyl oder Carboxyäthyl, Alkoxygruppen, wobei jede Alkoxygruppe 1 bis 5 C-Atome enthalten kann, zum Beispiel als Äthoxymethyl, Isopropoxymethyl-,· 2-Metnpxyäthyl, 2~Isopropoxyäthyl, 2-Butoxyäthyl, 2-Isobutoxyäthyl, 3-Pentoxypropyl. -. . . ".as 2-hydroxyethyl or 3-hydroxypropyl ,. Carboxy groups for Example as carboxymethyl or carboxyethyl, alkoxy groups, where each alkoxy group can contain 1 to 5 carbon atoms, for example as ethoxymethyl, isopropoxymethyl, · 2-methylpoxyethyl, 2 ~ isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 3-pentoxypropyl. -. . . ".
Ferner kommen als vorwiegend endständige Substituenten der Alkylgruppen mit 1 bis 5 C-Atcmen inf^age: Alkoxycarbonylgruppen mit 1 bis 5 C-Atomen im Alkoxyrest vuaö Carboxamidogruppen, bei denen der Stickstoff durch Alkylgruppen vorzugsweise mit 1 bis 5 C-Atomen mono- oder disubstituiert sein kann oder Bestandteil eines 4- bis 7-güedrigen Ringes ist. " --·-- Beispiele für Alkoxycarbonyl- und Carboxamidogruppen sind: Ä'thoxycarbonylmethyl, 2-Butoxycarbonyläthyl, Biäthylaaiinocarbonylmethyl, 2-Diäthylaminocarbonyläthyl, 2-Pyrrolidinocarbonyläthyl, Pipera7,inocarbonylmethyl usw. Alkylgruppen mit 1 bis 5 C-Atomen können auch, endständig substituiert sein mit Aminogruppen, bei denen der Stickstoff gegebenenfalls durch. Alkylgruppen mit vorzugsweise 1 bis 5 C-Atomen mono- oder disubstituiert sein kann oder Bestandteil eines 4- bis 7-6lit?-clrigen Ringes ist. Beispiele für N-substituierte Alkylgruppen sind: Aminomethyl, 2-Methylaminoäthyl, 2-Dimethylaniinoäthyl, 2-Diäthylaminoäthyl, 3-Dimethylaiuinopropyl, 3-Ä'thylmethylaminopropyl, Pyrrolidino, Piperidino, N-Methylpiperazinv,Furthermore, the following are predominantly terminal substituents of the alkyl groups with 1 to 5 carbon atoms: alkoxycarbonyl groups with 1 to 5 carbon atoms in the alkoxy radical, vuaö carboxamido groups, in which the nitrogen is mono- or disubstituted by alkyl groups, preferably with 1 to 5 carbon atoms can be or is part of a 4 to 7-güedrigen ring. "- · - Examples of alkoxycarbonyl and carboxamido groups are: ethoxycarbonylmethyl, 2-butoxycarbonylethyl, biäthylaaiinocarbonylmethyl, 2-diethylaminocarbonylethyl, 2-pyrrolidinocarbonylethyl, Pipera7, inocarbonylmethyl, etc. Alkyl groups with 1 to 5 C-atoms can also be substituted be with amino groups in which the nitrogen can optionally be mono- or disubstituted by alkyl groups with preferably 1 to 5 carbon atoms or is part of a 4- to 7-liter ring. Examples of N-substituted alkyl groups are: aminomethyl , 2-methylaminoethyl, 2-dimethylaniinoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl, 3-ethylmethylaminopropyl, pyrrolidino, piperidino, N-methylpiperazinv,
6 -6 -
709813/0970709813/0970
ti_l Vif Hvvt /Λν, Λ - Gewcibücher Rec!s'i,r.'-!i<.iirti_l Vif Hvvt / Λν, Λ - Gewcibücher Rec! S'i, r .'-! I <.iir
Hexamethylenimine» usw.Hexamethyleneimine »etc.
Palls Rn und/oder Rp in den .Verbindungen der allgemeinen Formel I für Cycloalkyl- bzw. Cycloalkyl-alkylgruppen stehen, enthalten diese vorzugsweise J bis 7 C-Atome. Bevorzugt;, sind die Cyclopropyl-, Cyclopropyl methyl-, Cyclopentyl- und Cyclohexylgruppen. ■Palls Rn and / or Rp in the .Verbindungen the general Formula I stand for cycloalkyl or cycloalkyl-alkyl groups, these preferably contain J to 7 carbon atoms. Preferred;, are the cyclopropyl, cyclopropyl methyl, cyclopentyl and cyclohexyl groups. ■
Palls R-. und/oder R~ für Aryl- oder Aralkylgruppen stehen, kommen insbesondere die Phenyl- und die Benzylgruppe infrage.Palls R-. and / or R ~ stand for aryl or aralkyl groups, The phenyl and benzyl groups are particularly suitable.
Bevorzugt sind die Verbindungen der allgemeinen Formel I, in denen Rp eine Methylgruppe darstellt.The compounds of the general formula I in which Rp represents a methyl group are preferred.
Die racemischen und optisch aktiven Verbindungen der allgemeinen I'ormei I sind wertvolle neuropsychotrope Heilmittel. Die neuen Verbindungen zeigen zentral-depressive, apomorphinantaganistischeund antihocizeptive Wirkung und weisen damit eine gewisse Ähnlichkeit zum Chlorpromazin auf (Literatur: Modem Problems of Pharmacopsychiatry, Volume 5, Seite 35-MA-: uanssen P.A.Y., "Chemical and Pharmacological Classification ofThe racemic and optically active compounds of the general formula I are valuable neuropsychotropic remedies. The new compounds show central-depressive, apomorphine antaganistic and antihociceptive effects and thus show a certain similarity to chlorpromazine (literature: Modem Problems of Pharmacopsychiatry, Volume 5, page 35- MA-: uanssen PAY, "Chemical and Pharmacological Classification of
■ - 7 709813/0970 ■ - 7 709813/0970
t~%f~~'*( ΗΓΓ'ΰ" IJ » fit > t ~ % f ~~ '* ( ΗΓΓ'ΰ " IJ » fit >
owl if—riif μοϊ nuowl if — riif μοϊ nu
~ *f - Ji Gcvv· '-"-ι·»·· »r-riiisscimtz ~ * f - Ji Gcvv · '- "- ι ·» ·· »r-riiisscimtz
Neuroleptics", edited, "by Bo'bon D.P. et al., S. Karger VetL^ Basel, München,Paris, New York (1970)). Andererseits unterscheiden sich die erfindungsgemäßen Verbindungen vom Chlorpromazin durch weniger ausgeprägte Reflexbeeinträchtigung, weniger ausgeprägte sedierende und narkotische Eigenschaften und andersartige Beeinflussung der Mogenen -fimine. -So besitzt zum Beispiel 4-(3,^~Dimethoxy-phenyl)-2-pyrrolidon .eine, gegenüber Chlorpromazin etwa 20fach schwächere barbitalschlafzeitverlängernde ¥ir3oing. · ■-.; ■-..= -..-- .·. - ■Neuroleptics ", edited," by Bo'bon DP et al., S. Karger VetL ^ Basel, Munich, Paris, New York (1970)). On the other hand, the compounds according to the invention differ from chlorpromazine by less pronounced impairment of reflexes, less pronounced sedative and narcotic properties and other types of influencing of the Mogene-Fimine. For example, 4- (3, ^ ~ dimethoxyphenyl) -2-pyrrolidone possesses an ir3oing which is about 20 times weaker than chlorpromazine and which prolongs the barbital sleep time. · ■ - .; ■ - .. = -..--. ·. - ■
Me neuen Verbindungen sind durch einen raschen Wirkungseintritt und geringe akute loxizität gekennzeichnet.Me new compounds are characterized by a rapid onset of action and low acute loxicity.
Insbesondere zeichnen sich die am Ringsticlcstoff mit einer O- oder N-substituierten Carbonylgruppe substitxiierten erfindungsgemaßen Verbindungen durch eine ausgeprägt protrahierte Wirkung bei gleichem Wirkungsspektrum aus.In particular, the rings on the ring fabric with an O- or N-substituted carbonyl groups according to the invention Compounds are characterized by a pronounced protracted effect with the same spectrum of activity.
~Die günstigen Eigenschaften der neuen Verbindungen waren nicht zu erwarten, da - wie eigene Versuche, zeigten - die entsprechenden p- bzw. m-monosubstituierten Phenyl-2-pyrrolidone ein anderes Wirkungsspektrum oder nur eine geringe Wirkung besitzen. ~ The favorable properties of the new compounds were not to be expected because - as our own experiments showed - the corresponding p- or m-monosubstituted phenyl-2-pyrrolidones have a different spectrum of activity or only have a minor effect.
Das in dem japanischen Patent 70 16 692 beschriebene 4-(4-Chlorphenyl)-2-pyrrolidon weist zum Beispiel antikonvulsive Wirkung auf. Die unsubstituierten Phenyl-2-pyrrolidone sind nur sehr schwach wirksam.4- (4-chlorophenyl) -2-pyrrolidone described in Japanese Patent 70 16 692 has anticonvulsant effects, for example. The unsubstituted phenyl-2-pyrrolidones are just very weakly effective.
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Aufgrund der oben beschriebenen Wirkungen können die erfindungsgemäßen Verbindungen in Form pharmazeutischer Präparate zur Behandlung-verschiedener' neurologischer-und psychischer- StörungenDue to the effects described above, the invention Compounds in the form of pharmaceutical preparations for Treatment of various neurological and psychological disorders
angewendet werden« Die Herstellung der Präparate erfolgt mit .den für die enterale oder parenterale Applikation üblichen Trägerstoffen, wie zum Beispiel Wasser, Alkohol, Gelatine, Gummi. arabicum, Müßhzucker, Stärke, Magnesiumstearat, Talkum, Ί- pflanzliche öle, Polyalkylenglykol usw. Die Präparate können in fester Form als Tabletten, Kapseln, Dragees, Suppositories oder in flüssiger Form als Lösungen, Suspensionen oder Emulsionen vorliegen. .The preparations are made with the usual carriers for enteral or parenteral administration, such as water, alcohol, gelatine, gum. arabic, sugar sugar, starch, magnesium stearate, talc, Ί- vegetable oils, polyalkylene glycol, etc. The preparations can be in solid form as tablets, capsules, dragees, suppositories or in liquid form as solutions, suspensions or emulsions. .
- 9 709813/0970 - 9 709813/0970
. "-.ν .\~\\—γ"»fs Vi ~i f-'i.'y Geiferb 1. liechtsschut.■. . "-.ν . \ ~ \\ -γ" »fs Vi ~ i f-'i.'y Geiferb 1. liechtsschut. ■.
Die neuen 4-(Polyalkoxy-phenyl)--2-pyrrolidone der allgemeinen Formel I können hergestellt werden, indem man in an sich bekannter WeiseThe new 4- (polyalkoxyphenyl) - 2-pyrrolidones of the general Formula I can be prepared by in a manner known per se
a) 4—(Substituiertes Phenyl)-2-pyrrolidon-3-carbonsäurealkylester der allgemeinen Formel IIa) 4- (Substituted phenyl) -2-pyrrolidone-3-carboxylic acid alkyl ester of the general formula II
COORCOOR
(H)(H)
worin R-,1 und Rp1 entweder R-, und R^ oder Wasserstoff bedeuten, R, die oben angegebene Bedeutung hat und R eine vorzugsweise niedere Acylgruppe darstellt, ■ . verseift und decarboxyliert oderwherein R-, 1 and Rp 1 are either R-, and R ^ or hydrogen, R, has the meaning given above and R is a preferably lower acyl group, ■. saponified and decarboxylated or
b) 3-(Substituiertes Phenyl)-4-amino-buttersäurealkylester der allgemeinen Formel IIIb) 3- (Substituted phenyl) -4-amino-butyric acid alkyl ester of the general formula III
CH2-COOR CH2-NH2 CH 2 -COOR CH 2 -NH 2
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(in) ,(in) ,
- ίο -- ίο -
ii-Λ Mt ^Vv! "*■ ~ *^ — Gewerbliche!· Rechtstdtisiz ii-Λ Mt ^ Vv! "* ■ ~ * ^ - Commercial! · Rechtsstdtisiz
worin E-,', 1^p'' ^ "^1^ -^ ^^e 0^011 angegebene Bedeutung haben, " öder ein Säureadditionssalz davon unter Alkoholabspaltung cyelisiert oder - -where E-, ', 1 ^ p''^"^ 1 ^ - ^ ^^ e 0 ^ 011 have the meaning given," or an acid addition salt thereof celiates with elimination of alcohol or - -
c) 3-(Substituiertes Phenyl)-4-amino-buttersäure der allgemeinen Pormel IV ... .c) 3- (Substituted phenyl) -4-aminobutyric acid of the general Formula IV ....
CH-CH2-COOH (IV)CH-CH 2 -COOH (IV)
worin E^1 , R2* und E, die oben angegebene Bedeutung haben, oder ein Säure additions salz davon unter Wasserabspaltung cyclisiert und in den nach a), b) oder c) erhaltenen Verbindungen die Iminogruppe (NH) alkyliert, aryliert oder acyliert und gegebenenfalls freie Hydroxygruppen (OR^1 oder OR ') alkyliert oder aryliert, gegebenenfalls den Carbonylsauerstoff gegen Schwefel austauscht und, falls Racemate optisch aktiver Verbindungen entstehen, diese gegebenenfalls einer Racematspaltung unterwirft.wherein E ^ 1 , R 2 * and E, have the meaning given above, or an acid addition salt thereof cyclized with elimination of water and the imino group (NH) alkylated, arylated or acylated in the compounds obtained according to a), b) or c) and optionally free hydroxyl groups (OR ^ 1 or OR ') alkylated or arylated, optionally exchanging the carbonyl oxygen for sulfur and, if racemates of optically active compounds are formed, these optionally subjecting them to a racemate resolution.
Zur Herstellung der Verbindungen der allgemeinen Formel I wendet man bekannte Methoden an.For the preparation of the compounds of general formula I. known methods are used.
- 11 -- 11 -
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-jicei-bl. Re cli tss elm t;-jicei-bl. Re cli tss elm t;
Die Verseifung gemäß Verfahren a) wird mit wäßrigem Alkali zweckmäßigerweise in einem mit Wasser mischbaren Lösungsmittel, zum Beispiel in einem Alkohol wie Äthanol, in Tetrahydrofuran oder Dioxan hei Temperaturen zwischen etwa 60 und 150 G, vorzugsweise "bei Siedetemperatur, durchgeführt. Die Decarboxylierung gemäß a) erfolgt durch Erhitzen der Carbonsäure auf etwa 160 bis 280°C. Vorzugsweise wird die Substanz im Vakuum erhitzt. Man kann die COp-Abspaltung gegebenenfalls auch in Gegenwart eines hochsiedenden inerten Lösungsmittels, wie zum Beispiel in Diphenyläther oder Chinolin, vornehmen.The saponification according to process a) is carried out with aqueous alkali, expediently in a water-miscible solvent, for example in an alcohol such as ethanol, in tetrahydrofuran or dioxane at temperatures between about 60 and 150 G, preferably "at the boiling point, carried out. The decarboxylation according to a) is carried out by heating the carboxylic acid to about 160 to 280.degree. Preferably the Substance heated in a vacuum. One can split off the COp optionally also in the presence of a high-boiling inert solvent such as diphenyl ether or quinoline, make.
Die Cyclisierung nach Verfahren b) wird unter Alkohol ab spaltung in einem organischen Lösungsmittel, wie zum Beispiel Dimethylformamid, Dimethylacetamid, Tetrahydrofuran, Dioxan, Benzol, Toluol, Xylol usw., unter Erhitzen auf etwa 50 bis 15?0°C bewirkt. Venn man von einem Salz, beispielsweise dem Hydrochlorid, des Aminosäureesters der allgemeinen !Formel III ausgeht, wird in Gegenwart einer tertiären Base erhitzt. Als tertiäre Basen sind Trialkylamine, wie zum Beispiel Triäthylamin und Tributylamin, aber beispielsweise auch N-Methylmorpholin, Diäthylcyclohexylaiiiin, Pyridin usw.. geeignet.The cyclization according to process b) is split off with alcohol in an organic solvent such as dimethylformamide, Dimethylacetamide, tetrahydrofuran, dioxane, benzene, toluene, xylene, etc., with heating to about 50 to 15? 0 ° C causes. If one uses a salt, for example the hydrochloride, of the amino acid ester of the general formula III goes out, is heated in the presence of a tertiary base. As a tertiary Bases are trialkylamines, such as triethylamine and Tributylamine, but also, for example, N-methylmorpholine, diethylcyclohexylaiiiin, Pyridine etc .. suitable.
-Nach Verfahren c) wird die Cyclisierung unter wasserabspaltung bei Temperaturen zwischen etwa 160 und 280 C vorgenommen. Es ist-According to process c), the cyclization is carried out with elimination of water made at temperatures between about 160 and 280 C. It is
-- 12 -- 12 -
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i i ~- ; WS V \..-*i 'ii ~ - ; WS V \ ..- * i '
günstig, im Vakuuia zu arbeiten, damit das abgespaltene Wao.ser leichter entfernt werden kann und der Zutritt von Luftsauerstoff unterbunden wird. Wenn man von den entsprechenden Säureadditxonssalzen ausgeht, wird wie unter b) in Gegenwart einer tertiären Base erhitzt.favorable to work in the Vakuuia so that the split off Wao.ser Can be removed more easily and the ingress of atmospheric oxygen is prevented. If one of the appropriate Acid addition salts run out, is heated as under b) in the presence of a tertiary base.
Die nach a), b) oder c) erhaltenen Verbindungen, in denen En 1, oder E^1 ein Wasserstoffatom bedeutet, müssen anschließend durch 0-Alkylierung in die Endprodukte der allgemeinen Formel I überführt werden. Die Alkylierung wird vorzugsweise mit dem entsprechenden Ε-,- bzw. Ep-halogenid oder -tosylat in an sich bekannter Weise durchgeführt. Als Halogenide sind die Chloride, Bromide und Jodide geeignet.·. Zur Alkylierung wird die Hydroxyverbindung beispielsweise in einem polaren Lösungsmittel gelöst und in Gegenwart einer Base mit dem Alkylierungsmittel auf Temperaturen zwischen 30 und 150°C erhitzt. Als Basen sind beispielsweise Natriumhydrid, Kaliumcarbonat, Alkai!alkoholate, wie Natriumäthylat, Kalium-butylat und Kalium-tert.-butylat, geeignet. Als polare Lösungsmittel kommen Dimethylformamid, Dimethylacetamid, Tetrahydrofuran, Dioxan, Ketone, wie Aceton und Methylisobutylketon, sowie Alkohole, wie Äthanol, Butanol und tert.-Butanol, infrage.The compounds obtained according to a), b) or c) in which E n 1 or E ^ 1 denotes a hydrogen atom must then be converted into the end products of general formula I by 0-alkylation. The alkylation is preferably carried out with the corresponding Ε -, - or ep halide or tosylate in a manner known per se. The chlorides, bromides and iodides are suitable as halides. For the alkylation, the hydroxy compound is dissolved, for example, in a polar solvent and heated to temperatures between 30 and 150 ° C. with the alkylating agent in the presence of a base. Suitable bases are, for example, sodium hydride, potassium carbonate, alkali alcoholates such as sodium ethylate, potassium butylate and potassium tert-butylate. Possible polar solvents are dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ketones such as acetone and methyl isobutyl ketone, and alcohols such as ethanol, butanol and tert-butanol.
13 -13 -
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.ttMr\ I.tt M r \ I
it-» lsi \jtwiit- »lsi \ jtwi
Gewerblicher RechtsschutzIntellectual Property
Alkylierung, Arylierung oder Acylierung der Iminogruppe erfolgen ebenfalls nach bekannten Methoden. So wird die Iininoverbindung (E^ =H) in einem polaren Lösungsmittel gelöst und in Gegenwart eines Salzbildners mit einem Alkyl-, Aryl- oder Acylhalogenid auf etwa 40 bis I50 C erhitzt. Als polare Lösungsmittel können Dimethylformamid, Dimethylacetamid, Tetrahydrofuran, Idoxan, Ketone, wie Aceton und Methylisobutylketon, sowie Alkohole, wie Äthanol und But and, verwendet werden. Geeignete Salzbildner sind zum Beispiel liatriumhydrid, Kaliumcarbonat, Alkali alkohol ate, wie Natriumäthylat, Kalium-tert.-butylat usw. Die Umsetzung mit Halogenaryl, beispielsweise -Jodbenzol, kann auch ohne Lösungsmittel, vorzugweise in Gegenwart von Kupferpulver, durchgeführt werden.Alkylation, arylation or acylation of the imino group are also carried out according to known methods. This is how the Inino compound (E ^ = H) dissolved in a polar solvent and in the presence of a salt former with an alkyl, aryl or acyl halide heated to about 40 to 150 ° C. As polar Solvents can be dimethylformamide, dimethylacetamide, tetrahydrofuran, Idoxane, ketones such as acetone and methyl isobutyl ketone, and alcohols such as ethanol and butene can be used. Suitable salt formers are, for example, lithium hydride, potassium carbonate, Alkali alcohol ate, such as sodium ethylate, potassium tert-butylate etc. The reaction with haloaryl, for example iodobenzene, can also be carried out without a solvent, preferably in the presence of copper powder.
Bei der Umsetzung mit einem Halogenkohlensäureester, wie z.B. Chlorkohlensäurealkyl- oder arylester, kann man auf das Lösungsmittel verzichten und läßt längere Zeit bei erhöhter Temperatur in Gegenwart eines Alkalicarbonate, wie Natriumcarbonat, reagieren.When reacting with a halocarbonic acid ester, such as chlorocarbonic acid alkyl or aryl ester, one can rely on the Do without solvents and leave for a long time at elevated temperature in the presence of an alkali metal carbonate, such as sodium carbonate, react.
Setzt man die Iminoverbindung mit einem Isocyanat zu Carbaminsäurederivaten um, so können inerte Lösungsmittel wie halogenierte Kohlenwasserstoffe, z.B. Methylenchlorid oder Chloroform, verwendet werden.If the imino compound is combined with an isocyanate to form carbamic acid derivatives Inert solvents such as halogenated hydrocarbons, e.g., methylene chloride or chloroform, can be used will.
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Gewerbiidiur Rechtssc'n \z Gewerbiidiur Rechtssc'n \ z
•Der Austausch von Carbonylsauerstoff, gegen Schwefel wird In derselben Weise durchgeführt, wie er in der Literatur für der- _artige Verbindungen beschrieben ist. (Vergleiche hierzu J. W. Scheeren, P.H.J. Ohms, E.J.5'. Mlvard, Synthesis 1973, 149-151).• The exchange of carbonyl oxygen, for sulfur is in the same Carried out in the manner described in the literature for the _like connections is described. (Compare with J. W. Scheeren, P.H.J. Ohms, E.J. 5 '. Mlvard, Synthesis 1973, 149-151).
Kir diesen Zweck ist beispielsweise ein Polysulfid wie Phosphorpentasulfid in einem Lösungsmittel oder "Lösungsraittelgemiscii -in Gegenwart einer Base geeignet. Die Umsetzung kann auch in einer Suspension vorgenommen werden. Geeignete Lösungs- bzw. Suspensionsmittel sind zum. Beispiel Acetonitril, (!tetrahydrofuran, Diäthyläther, Glykoldlniethyläther. Als Basen sind Uatriumhydrogencarbonat, Kaliumcarbonat usw. geeignet. Die Umsetzung ist bei JO bis 1200C nach 3 "bis 24 Stunden beendet.For this purpose, for example, a polysulfide such as phosphorus pentasulfide in a solvent or solvent mixture in the presence of a base is suitable. The reaction can also be carried out in a suspension. Suitable solvents or suspending agents are, for example, acetonitrile, (tetrahydrofuran, diethyl ether, Glykoldlniethyläther. suitable bases Uatriumhydrogencarbonat, potassium carbonate, etc. are suitable. The reaction is completed at JO to 120 0 C by 3 "to 24 hours.
709813/0970709813/0970
- 3^5 - . - - Gev.rerl>X., Re ctits schul v - 3 ^ 5 -. - - Gev. r erl> X., Re ctits schul v
Die Ausgang,^verbindungen der Formeln II, III und IV'können ebenfalls nach "bekannten Methoden, zum Beispiel auf folgende Weise hergestellt werden.The starting compounds of formulas II, III and IV can be used also by "known methods, for example in the following manner.
Ausgehend von dem durch E-^1, ILj' i ^x substituierten Benzaldehyd wird mit Maloiisäuredialkylester der entsprechende Benzal-malonsäuredialkylcster hergestellt. Der substituierte Benzal-malonsäuredialkylester kann mit Nitromethan in Gegenwart von Tetramethylguanidin über 1-(Substituiertes Phenyl)-2-nitroäthylmalonsäuredialkylester und anschließende Druckhydrierung unter Verwendung von Raney-Nickel in 4-(Substituiertes Phenyl)-2-pyrrolidon-3-carbonsäurealkylester der allgemeinen Formel II überführt werden.Starting from the benzaldehyde substituted by E- ^ 1 , ILj'i ^ x, the corresponding dialkyl benzalmalonate is prepared with dialkyl malolate. The substituted benzal malonic acid dialkyl ester can with nitromethane in the presence of tetramethylguanidine over 1- (substituted phenyl) -2-nitroethylmalonic acid dialkyl ester and subsequent pressure hydrogenation using Raney nickel in 4- (substituted phenyl) -2-pyrrolidone-3-carboxylic acid alkyl ester of the general formula II to be transferred.
Zur Herstellung von 3~(Substituiertes Phenyl)-4-amino-buttersäur ealkylester der allgemeinen Formel III wird an die Doppelbindung des Benzal-malonsäurediesters mit Käliumcyanid in wäßrigem Alkohol unter Erwärmen auf 60 C HCN angelagert unter gleichzeitiger Abspaltung einer Carbalkoxygruppe, und die Cyanoverbindung wird in Gegenwart von Platindioxid unter Druck hydriert. Wird die HCN-AnIagerung in der Siedehitze durchgeführt, so entsteht die entsprechende Buttersäure der allgemeinen Formel IV*For the production of 3 ~ (substituted phenyl) -4-aminobutyric acid Alkyl ester of the general formula III is attached to the double bond of the benzal malonic acid diester with potassium cyanide in aqueous alcohol is added with heating to 60 C HCN with simultaneous splitting off of a carbalkoxy group, and the cyano compound is hydrogenated under pressure in the presence of platinum dioxide. If the HCN addition is carried out at the boiling point, so the corresponding butyric acid of the general formula IV * is formed
Die Umsetzungen von substituierten Benzaldehyd zu den Verbindungen II, III und IV seien anhand des folgenden Reaktionsschenas noch einmal erläutert:The reactions of substituted benzaldehyde to the compounds II, III and IV are based on the following reaction scheme explained again:
■ - 16 -■ - 16 -
709813/0970709813/0970
H .» kk* M ***** iH ." kk * M ***** i
- ytt ~ - ytt ~
Gewerbl. Rechti.t.cliut.Commercial Rechti.t.cliut.
CHOCHO
OR1 1 OR 1 1
R^OR ^ O
CH=CCH = C
COORCOOR
COORCOOR
ECNECN
OR1'OR 1 '
R2 1OR 2 1 O
R-zR-z
CH-CH^
2-N02 CH-CH ^
2 -N0 2
COORCOOR
R2 J0R 2 J 0
R, CH-CH2COOR CNR, CH-CH 2 COOR CN
IIII
III R = AlkylIII R = alkyl
IV R = HIV R = H
13/097013/0970
- Geverbl.Rechtsschut- Faded legal protection
Im folgenden werden die Verfahren näher "beschrieben.The procedures are described in more detail below.
Unter üblicher Aufarbeitung vjird Extraktion mit dem angegebenen Lösungsmittel, Vaschen der organischen Phase mit gesättigter Kochsalzlösung, Trocknen über wasserfreiem Calciumsulfat und Eindampfen im Vakuum bei einer Badteji<perat.ur von 4-O-45°C verstanden. Auf zusätzliche Behandlung der organischen Phase, wie Waschen mit Säure oder Lauge, wird besonders hingewiesen.With the usual work-up, extraction is carried out with the specified Solvent, washing the organic phase with saturated sodium chloride solution, drying over anhydrous calcium sulfate and Evaporation in vacuo at a Badteji <perat.ur of 4-045 ° C Understood. For additional treatment of the organic phase, such as washing with acid or alkali, is particularly pointed out.
Die angegebenen Ausbeuten sind keine optimalen Werte, Es wurden keine Optimierungsversuche unternommen.The yields given are not optimal values. No attempts at optimization were made.
Die Temperaturen werden Jeweils in Grad Celsius (0C) angegeben.The temperatures are given in degrees Celsius ( 0 C).
Die als Rohprodukt ausgewiesenen Substanzen wurden durch Dünnschichtchromatographie in mindestens 2 Systemen und mit Hilfe von IR-Spektren auf ausreichende Reinheit geprüft. Alle anderen Substanzen sind analysenrein (C-, H-, N-BeStimmungen; IR-, UV- und HMR-Sp ek tr en; Dünnschichtchromatographie; zum Teil Titrationen und Gaschromatographie).The substances identified as the crude product were determined by thin layer chromatography Checked for sufficient purity in at least 2 systems and with the help of IR spectra. All other substances are analytically pure (C, H, N determinations; IR, UV and HMR spectra; Thin layer chromatography; partly Titrations and gas chromatography).
Hinter dem auf der Koflerbank bestimmten Schmelzpunkt sind die zur Umkristallisation benutzten Lösungmittel in ( ) angegeben.Behind the melting point determined on the Kofler bench are the solvents used for recrystallization are indicated in ().
- 18 -- 18 -
709813/0970709813/0970
Gc verb X <. Recht:sncGc verb X <. Right: snc
Fire Lösungsmittel werden folgende Abkürzungen verwendet:Fire solvents, the following abbreviations are used:
Die Verbindungen der allgemeinen Formel II können beispielsweise wie folgt hergestellt werden:The compounds of general formula II can, for example can be produced as follows:
A) Benzal-malonsäurediäthylester A) Benzal malonic acid diethyl ester
1 Mol eines entsprechend substituierten Benzaldehyds wird mit 160 g Malonsäurediäthylester (1 Mol), 30 ml Eisessig und 3 Piperidin in 1 leiter Benzol bis zur Abspaltung eines Moles Wasser am Wasserabscheider erhitzt. Die benzolische Lösung wird wie üblich aufgearbeitet.1 mole of an appropriately substituted benzaldehyde is with 160 g of malonic acid diethyl ester (1 mol), 30 ml of glacial acetic acid and 3 Piperidine in 1 line of benzene heated on a water separator until a mole of water is split off. The benzene solution is processed as usual.
Der in der Literatur noch nicht beschriebene 3-Jsobutoxy-4-Eiethoxy-benzaldehyd
wird wie folgt hergestellt:
108 g 3-Hydroxy-4-.metho:xy-benzaldehyd (710 mMol) werden mit
40.5 S Kaliumhydrorxyd (723 mMol) uud 120 g Isobutylbromid
(875 mMol) in 250 m Ithanol unter Rühren 26 Stunden zum
Siecien erhitzt. Nach Abdestillier en des Alkohols im Vakuum
wird der Rückstand wie üblich mit Essigester aufgearbeitet, aber zusätzlich mit 2 η Natronlauge gewaschen. Aus demThe 3-isobutoxy-4-ethoxy-benzaldehyde not yet described in the literature is prepared as follows:
108 g of 3-hydroxy-4-metho: xy-benzaldehyde (710 mmol) are mixed with 40.5 S potassium hydroxide (723 mmol) and 120 g of isobutyl bromide (875 mmol) in 250 ml of ethanol with stirring for 26 hours
Siecien heated. After the alcohol has been distilled off in vacuo, the residue is worked up as usual with ethyl acetate, but additionally washed with 2 η sodium hydroxide solution. From the
709813/0970 " 19 "709813/0970 " 19 "
Gewerbl.RechtsschtCommercial law
alkalischen Extrakt werden durch Ansäuern 35 S Ausgangsmaterial
zurückgewonnen. Die Ausbeute an 3-Iso"butoxy-4-metnoxy-ti
enz aldehyd beträgt 80 g.
Schmelzpunkt: 70° (Heptan).alkaline extract are recovered by acidifying 35 S starting material. The yield of 3-iso "butoxy-4-metnoxy-ti enz aldehyde is 80 g.
Melting point: 70 ° (heptane).
In der folgenden Tabelle sind die Ausbeuten und die Siede- bzw. Schmelzpunkte einiger Verbindungen zusammengestellt. The table below shows the yields and the boiling and melting points of some compounds.
- 20 -- 20 -
709813/0970 "709813/0970 "
ί—'f—t-_-ff\ :■-" i ί —'f — t -_- ff \: ■ - " i
tt—I ill '.^Λ ίtt — I ill '. ^ Λ ί
Gewerbl.. licchtspchutCommercial. Licchtspchut
-CH=C--CH = C-
V R.
V
E2-3
E 2 -
(% d. Theorie)yield
(% of theory)
Schmelzpunkt
(Umkristalli-
sationsmittel)Boiling point,
Melting point
(Recrystalline
sation agent)
3-CH,.
3
v/xIqOJI/)
I --- / TtT Γ · ΤΤ -
v / xIqOJI /)
I ---
3-CH,
3
c 3 *- 3-CH O CH (CH,) O - -CH,
c 3 * - 3
P. 86° (DIP)K 1 213-215 0 C
P. 86 ° (DIP)
3-CH,
3
32-0CH, 10O
3
- 21 -- 21 -
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Ge we rbl.Rechtsschute - SA- -Commercial lawyers - SA- -
JfCJfC
B) !-(Substituiertes Phenyl)-2-nitroäthyl-malonsäürediäthylester 5OO mM des entsprechenden Benzalmalonsäurediäthylesters (siehe A) werden in 250 ml Nitromethan gelöst und unter Rühren bei 0° mit 12,7 dlL Tetramethylguanidin versetzt. Nach Abklingen der exothermen Reaktion läßt man noch 18 Stunden bei Raumtemperatur rühren. Die Reaktionsmischung wird wie üblich mit Essigester aufgearbeitet, aber zusätz-. lieh mit 2 η Salzsäure gewaschen. Die für die Beispiele B b und B c erforderlichen Acetoxy-methoxy-behzal—aialonester werden wie folgt hergestellt:B) ! - (Substituted phenyl) -2-nitroethyl malonic acid diethyl ester 500 mM of the corresponding benzalmalonic acid diethyl ester (see A) are dissolved in 250 ml of nitromethane and 12.7 dlL of tetramethylguanidine are added while stirring at 0 °. After the exothermic reaction has subsided, the mixture is stirred for a further 18 hours at room temperature. The reaction mixture is worked up as usual with ethyl acetate, but additionally. borrowed washed with 2 η hydrochloric acid. The acetoxy-methoxy-behzal-aialon esters required for Examples B b and B c are prepared as follows:
150 g (3-Hydroxy-4-methoxy-benzal)-malonsäurediäthylester (5IO mMol),(s. Ae) werden in 450 ml Pyridin gelost, und unter Eiskühlung werden 57 ml Essigsäureanhydrid (604 mM) zugetropft. Nach 18-stündigem Stehen bei Raumtemperatar wird das Pyridin im Vakuum abgezogen. Die übliche Aufarbeitung mit Essigester ergibt 163 g (3~Acetoxy-4-methoxy-benzal)-malonsäurediäthylester (95 % eier Theorie) Schmelzpunkt: .75-77° (Diisopropyläther).150 g (3-hydroxy-4-methoxy-benzal) malonic acid diethyl ester (5IO mmol), (see Ae) are dissolved in 450 ml of pyridine, and under 57 ml of acetic anhydride (604 mM) are added dropwise to ice cooling. After standing for 18 hours at room temperature, the pyridine is stripped off in vacuo. The usual work-up with ethyl acetate gives 163 g of (3 ~ acetoxy-4-methoxy-benzal) malonic acid diethyl ester (95% of theory) Melting point: 75-77 ° (diisopropyl ether).
Analog wird das .(4-Hydroxy-3-methoxy-benzal)-malonat (s. A f) ziu? entsprechenden 4-Acetoxy~3-methoxy-Verbindung acetyliert. Ausbeute: 95 %· Schmelzpunkt: 51 ° (Diisopropyläther-Petroläther). (4-Hydroxy-3-methoxy-benzal) -malonate (see A f) ziu? corresponding 4-acetoxy ~ 3-methoxy compound acetylated. Yield: 95 %. Melting point: 51 ° (diisopropyl ether-petroleum ether).
- 22 -- 22 -
709813/0970709813/0970
CH-CHCH-CH
■ COOCJL■ COOCJL
Gewerbl.ReehtsschmCommercial Reehtsschm
(% der
Theorie)yield
(% the
Theory)
(Umkristalli-
sationsmittel)Melting point
(Recrystalline
sation agent)
O -COCH,
O
5-CH,
5
chlorid-DIP)75 ° (methylene
chloride DIP)
an SiO2
(Cyclohexan-Essig-
ester 1:1)ChroB? at ographi e
of SiO 2
(Cyclohexane vinegar
ester 1: 1)
SiO2
(Cyclohexan-Essig-
ester 1 :. 1)Chromatography
SiO 2
(Cyclohexane vinegar
ester 1:. 1)
- 23 -- 23 -
709813/0970709813/0970
C) 7I-(öubötituiertes Phenyl)-2-χ·;ν>.ττο3.:ΐ•"'loii-ii-car'bor.^aurt. -ulhuL o»tor (II) . C) 7 I- (substituted phenyl) -2-χ ·; ν > .ττο3.: Ϊ́ • "'loii-ii-car'bor. ^ Aurt. -UlhuL o» tor (II).
cl: υ ίcl: υ ί
3OO iflliol dos entsprechenden l-Phenyl-2-nitro-äthyl-malonsäure-diäthylesters werden in 7OO ml Methanol gelöst und mit ca. 10 g Raney-Nickel "bei 60 und 95 Atmosjpliären Druck "bis zur Aufnalime von 3 Mol Wasserstoff hydriert. Anschließend wird vom Katalysator abfiltriert, im Vakuum eingeengt und der ölige Rückstand umkristallisie^t.3OO iflliol dos corresponding l-phenyl-2-nitro-ethyl-malonic acid diethyl ester are dissolved in 7OO ml of methanol and with approx. 10 g Raney nickel "at 60 and 95 atmospheric pressure "Hydrogenated until 3 moles of hydrogen were absorbed. Then the catalyst is filtered off, concentrated in vacuo and the oily residue recrystallized.
709813/0970709813/0970
Gf.ivei"bl. I?f-ci = ί £ sei«Gf.ivei "bl. I? F-ci = ί £ is«
($> der Tlieorie)yield
($> of the Tlieorie)
(Unücri st alii sation
mittel)Melting point
(Unücri st alii sation
middle)
(Abspaltung der
Acetylgruppe bei
Hjrdrierung und
Aufarb e i tung)125 ° (EE-DIP)
(Spin-off of
Acetyl group
Hydrogenation and
Preparation)
5 -COCH,
5
P -2--0CH x
P.
>e K) H x
>
70 9813/097070 9813/0970
Gewertil.Rechtsschut;Legal protection;
Die Verbindungen der allgemeinen Formel III können zum Beispiel auf folgende V/eise hergestellt werden:The compounds of the general formula III can be prepared, for example, in the following way:
D) 3~(Substituiertes Phenyl)-3-cyano-propionsäure-::äthylester - 100 mM eines entsprechenden Benzal-malonesters (siehe A) werden in 180 ml Äthanol mit der Lösung von 6,5 S Kaliumcyanid (100 mMol) in 2p ml Wasser versetzt und 7 Stunden auf 60 C erwärmt. Nach 18-stündigem Stehen bei Raumtemperatur werden die Lösungsmittel im Vakuum abgezogen und der Rückstand in der üblichen V/eise mit Essigester einschließlich einer Extraktion mit 1 η natronlauge aufgearbeitet. Aus dem Natronlauge extrakt lassen sich gegebenenfalls durch Ansäuern die entsprechenden 3-Kienyl-3-cyano~propionsäuren erhalten.D) 3 ~ (Substituted phenyl) -3-cyano-propionic acid :: ethyl ester - 100 mM of a corresponding benzal malonic ester (see A) are in 180 ml of ethanol with a solution of 6.5 S potassium cyanide (100 mmol) in 2p ml of water are added and the mixture is heated to 60 ° C. for 7 hours. After standing for 18 hours at room temperature, the solvents are stripped off in vacuo and the residue is worked up in the usual way with ethyl acetate including extraction with 1 η sodium hydroxide solution. The corresponding 3-kienyl-3-cyano ~ propionic acids can optionally be obtained from the sodium hydroxide extract by acidification.
- 26 -- 26 -
7098 13/09707098 13/0970
6 e ν; ■■ · ' - 'ι „ j! V c L ΐ f -. c i ι j6 e ν; ■■ · '- ' ι "j! V c L ΐ f -. ci ι j
-CH-CH2-COOG2H5 CN-CH-CH 2 -COOG 2 H 5 CN
(% der Theorie;yield
(% of theory;
Bphrnclzpurkt,
Uinki'i stalD.i sation a
mittelBoiling point,
Bphrnclzpurkt,
Uinki'i stalD.i sation a
middle
P-CH-,
P.
I-CHpCHp-
I.
wXl/-. \s - OTJ Γ 1
wXl / -. \ s
P-CH x
P.
P-CH x
P.
- 27 -- 27 -
709813/0970709813/0970
8*7 - Ge t-re rb 1» He c lii £.: s c hxi t:8 * 7 - Ge t-re rb 1 »He c lii £ .: s c hxi t:
E) 3~(Substituiertes Plienyl)-4-amiiio-buttersäure-äthylesterhydrοchlorid (III) ^ E) 3 ~ (Substituted plienyl) -4-amiiio-butyric acid ethyl ester hydrochloride (III) ^
50 HiM eines 3-PJh.enyl-3~cyano-propionsäureäthylesters werden in 60 ml Eisessig über 1 g Platinoxid bei Raumtemperatur und 100 Atmosphären bis zur Aufnahme von 2 Mol Wasserstoff hydriert, es wird vom Katalysator:,.abgesaugt und nach Zugabe von 25 ml 2 11 inethanolischer Salzsäure im Vakuum auf ein kleines Volumen • eingedampft. · · - · - ' ■ \50 HiM of a 3-PJh.enyl-3 ~ cyano-propionic acid ethyl ester hydrogenated in 60 ml of glacial acetic acid over 1 g of platinum oxide at room temperature and 100 atmospheres until 2 moles of hydrogen are absorbed, it is sucked off by the catalyst:,. and after adding 25 ml 2 11 inethanolic hydrochloric acid in vacuo to a small volume • evaporated. · · - · - '■ \
- 28 -- 28 -
7 09813/09707 09813/0970
t—< tr \i~ '. t— <tr \ i ~ '.
- aC -- aC -
CH-CH2-COOC2H5 CH2HH2-HClCH-CH 2 -COOC 2 H 5 CH 2 HH 2 -HCl
■-ice rbl. lic c ht s κ■ -ice rbl. lic c ht s κ
-CHx
z> -CH-,
-CH x
z>
(% der
Theorie)yield
(% the
Theory)
(Umkri st al1i-
sationsmittel)Melting point
(Umkri st al1i-
sation agent)
-GH,-CH 2 CH (CI
-GH,
£ d
£
5-OCH3 -H
5-OCH 3
Rohprodukt (DC,F. 124 ° (EE)
Crude product (TLC,
- 29 -- 29 -
709813/0970709813/0970
i-yi it. _► Vt-. ν.ν. <·," i~\-Js: i-yi it. _► Vt-. ν.ν. <·, " I ~ \ -Js:
Gewe'rbl.Rechts&chutr.Gewe'rbl.Rechts & chutr.
Die Verbindungen der allgemeinen Formel -IY lassen sich wie folgt herstellen: -The compounds of the general formula -IY can be like produce as follows: -
i1) 3~(Substituiertes Phenyl)-$-cyano-propionsäure i 1 ) 3 ~ (Substituted phenyl) - $ - cyano-propionic acid
Durch Umsetzung eines entsprechend substituierten Benzalmalcnesters (siehe unter A) mit Kaliuincyanid in gleichen Mengenverhältnissen und gleichen Reaktionszeiten,'..wie unter D beschrieben, jedoch in der Siedehitze, v/erden die 3~(Substituiertes Phenyl)~3-cyano-propionsäuren erhalten. Sie werden nach Abdampfen der Lösungsmittel, Aufnehmen des Rückstandes in Wasser, Waschen mit Essigester und Ansäuern der wäßrigen Phase isoliert und durch Kristallisation gereinigt.By converting an appropriately substituted Benzalmalc ester (see under A) with potassium cyanide in the same way Quantitative proportions and the same reaction times, '.. how Described under D, but at the boiling point, the 3 ~ (substituted phenyl) ~ 3-cyano-propionic acids are obtained. After the solvents have evaporated, the residue is taken up in water, washed with ethyl acetate and acidified isolated from the aqueous phase and purified by crystallization.
- 30 709813/0970 - 30 709813/0970
(~\S ■»! JS " t HK 1 ' · './■>. (~ \ S ■ »! JS " t HK 1 '·'./■>.
OVj; Ί.'ΙΙΓΙΗ V'·. Λ /"VxUOVj; Ί.'ΙΙΓΙΗ V '·. Λ / "VxU
^CH-CH2-COOH
CN^ CH-CH 2 -COOH
CN
P -CH x
P.
(% der
Theorie)yield
(% the
Theory)
(Umkri stalli-
sationsmittel)Melting point
(Umkri stalli-
sation agent)
- 31 -- 31 -
709813/0970709813/0970
^ 5 A ι 8 5 5^ 5 A ι 8 5 5
G) ^-(feubstituiertes Phenyl)-^-amino-butter'aaure-liydrochlorid (IV) 100 mil 3-(Substituiertes Phenyl)-3-cyano~propionsäure (siehe F) werden in 200 ml Eisessig unter Zusatz von 955'ml konzentrierter Salzsäure über 3 g Platindioxyd bei Raumtemperatur uud 100 Atmosphären bis zur Aufnahme von 2 Mol Wasserstoff hydriert. Es wird vom Katalysator abfiltriert und in Vakuum eingedampft. Durch Kristallisation des meist öligen Rückstandes werden die 3-(Substituiertes Phenyl)-4-aminobubtersäure-hydrochloride erhalten.G) ^ - (feubstituierte s, phenyl) - ^ - amino-butt er'aaure-liydr ochlorid (IV) 100 mil 3- (substituted phenyl) -3-cyano ~ propionic acid (see F) in 200 ml of glacial acetic acid with addition of 9 5 5 ml of concentrated hydrochloric acid is hydrogenated over 3 g of platinum dioxide at room temperature and 100 atmospheres until 2 moles of hydrogen are absorbed. The catalyst is filtered off and evaporated in vacuo. The 3- (substituted phenyl) -4-aminobutyric acid hydrochlorides are obtained by crystallization of the mostly oily residue.
709813/0970709813/0970
- 4h -- 4h -
G) E2 1OG) E 2 1 O
-CH-CH--COOH C-CH-CH-COOH C
3-CH 7
3
(% der
Theorie)yield
(% the
Theory)
(Uiakristalli-
sationsm:" ttel)Schmel zpimirb
(Uiacrystalline
sationsm: "ttel)
- 33 -- 33 -
709813/0970709813/0970
J-f 'L-ΐί_Ε Si-- if - Jf 'L-ΐί_Ε Si-- if -
-■■».-^s te. ϊ V-E v-<-.->"- ■■ ».- ^ s te. ϊ VE v - <-.->"
2,21 g 4-(3.'i-DiraetIioxy-phenyl)-2-pyrrolidon (lO niM.) werden mit 1 g wasserfreiem Natriumcarbonat und 30 »1 Chlorkohlensäureäthylester l6 Stunden bei 100 °C gerührt, anschließend filtx-iert und im Vakuum eingedampft. Man erhält 1*09 g 4- ( 3 . ^-Diniethoxy-phenyl)-2~pyrrolidon-l-carbonsäureäthyl~ ester vom Schmelzpunkt 88-90 C (Essigester/Petroläther) „2.21 g of 4- (3.'i-DiraetIioxy-phenyl) -2-pyrrolidone (10 niM.) Become with 1 g of anhydrous sodium carbonate and 30 »1 of ethyl chlorocarbonate Stirred for 16 hours at 100 ° C., then filtered and evaporated in vacuo. 1 * 09 g is obtained 4- (3. ^ -Diniethoxyphenyl) -2 ~ pyrrolidone-1-carboxylic acid ethyl ~ ester with a melting point of 88-90 C (ethyl acetate / petroleum ether) "
2,21 £ 4-(3.4-Dimethoxy-phenyl)-2-pyrrolidon werden eaialog Beispiel 1 mit ChlorkohlensäxirefcenzyXester umgesetzt und durch Chromatographie an Kieselgel mit Benzol/Essigester (1:1) gereinigt. Mar», erhält 1,24 g %-( 3« 4-Dimethoxy-phenyl)-2-pyrrolidon-l-carbonsäurebenzylester vom Schmelzpunkt 86-87 C (Essigester/Petroläther).2.21 £ 4- (3,4-dimethoxyphenyl) -2-pyrrolidone are reacted in Example 1 with chlorinated carbon dioxide and purified by chromatography on silica gel with benzene / ethyl acetate (1: 1). Mar », receives 1.24 g% - (3« 4-dimethoxyphenyl) -2-pyrrolidone-1-carboxylic acid benzyl ester with a melting point of 86-87 ° C. (ethyl acetate / petroleum ether).
0,221 g 4-(3.4-Dxmethoxy-phenyl)-2-pyrrolidon werden, in 10 ml Methylenchlorid mit 3 nil Chlorsulfonylisocyanat versetzt und 1,5 Stunden bei Raumtemperatur gerührt. Der Aasata wird wie üblich mit Methyleitchlorid aufgearbeitet und durch Säulenchromatogrc.phie an Kieselgel mit Chloroform/Aceton (l:l) gereinigt. Man erhält OfO26 g 4-(3.4-Dimethoxy-phenyl)-2-pyrrolidon-l~carbonsäureamid vom Schmelzpunkt 125-127 C (Methanol).0.221 g of 4- (3,4-methoxyphenyl) -2-pyrrolidone are mixed with 3 nil of chlorosulfonyl isocyanate in 10 ml of methylene chloride and the mixture is stirred at room temperature for 1.5 hours. The Aasata is worked up as usual with methyl chloride and purified by column chromatography on silica gel with chloroform / acetone (1: 1). O f O26 g of 4- (3,4-dimethoxyphenyl) -2-pyrrolidone-l-carboxamide with a melting point of 125-127 ° C. (methanol) are obtained.
- 34 -- 34 -
!WSPECTED! WSPECTED
709813/0970709813/0970
v>\.■·: L*_i »ei v.*v> \. ■ ·: L * _i »ei v. *
S3S3
4-{ 3»4-Dinie thoxy-phenyl) -2-pyrrolidon-l-carboiisäiirc amide 2,21 g 4- (3·4-Dimechoxy-phenyl)-2-pyrrolidon werden mit e Isocyanat der allgemeinen Formel R-NCO im Überschuß (ca. 1Ofache Menge) 2,5 Stunden zum Sieden erhitzt und an schließend im Vakuum eingedampft. 4- {3 »4-Dinieth oxy-phenyl) -2-pyrrolidone- 1-carb oiisä iirc amide 2.21 g of 4- (3 · 4-dimechoxyphenyl) -2-pyrrolidone are with e isocyanate of the general formula R-NCO in excess (about 10 times the amount) heated to boiling for 2.5 hours and then evaporated in vacuo.
In Abhängigkeit vom verwendeten Isccyaiiat werden folgende !-Carbonsäureamide erhalten:Depending on the Isccyaiiat used, the following ! -Carboxamides obtained:
(Umkristallisationsmittel)Melting point
(Recrystallization agent)
-CH^ ·*
XiH -CH 3
-CH ^ * *
XiH
1,53 g
2,62 g1.47 g
1.53 g
2.62 g
IO5-IO7 ° (EE-Petroläther)
110-112° (EE-Petroläther)95-98 ° (EE-DIP)
IO5-IO7 ° (EE petroleum ether)
110-112 ° (EE petroleum ether)
- 35 -- 35 -
ORfGiNAL INSPECTEDORfGiNAL INSPECTED
709813/0970709813/0970
15 Si' I 15 Si ' I
2,78 g h~ ( 3 . 4-Dirne thoxy-phenyl) -E-pjrrolidon-l-carbonsäuremethylamid (10 mM) werden in 20 ml Dimethylformamid bei 0 C lint er Rühren mit 0,5 g Natriumhydrid (50 5^ig) versetzt. Nach Beendigung der Wasserstoff entwickliang werden 1,27 g Benzylchlorid zugetropft iind l6 Stunden bei Raumtemperatur gerührt. Man dampft das Lösungsmittel im Vakuum ab und arbeitet wie üblich mit Essigester auf. Man erhält 1,58 g 4-(3.4-Dimethoxyphenyl)-2-pyrrolidon-l-carbonsäure-N-benzyl-methylamid vom Schmelzpunkt 76-78 °C (EE-DIP).2.78 g of h ~ (3. 4-dirne thoxyphenyl) -E-pyrrolidone-1-carboxylic acid methylamide (10 mM) are stirred in 20 ml of dimethylformamide at 0 ° C. with 0.5 g of sodium hydride (50% strength) ) offset. When the evolution of hydrogen has ceased, 1.27 g of benzyl chloride are added dropwise and the mixture is stirred at room temperature for 16 hours. The solvent is evaporated off in vacuo and worked up as usual with ethyl acetate. 1.58 g of 4- (3,4-dimethoxyphenyl) -2-pyrrolidone-1-carboxylic acid-N-benzyl-methylamide with a melting point of 76 ° -78 ° C. (EE-DIP) are obtained.
709813/0970709813/0970
Vorstand; Dr. Christian Brulin · K^ns-Jütgrn Hamann · Dr Heinz Hannse ' Postan-^irilt: CCHERING AG -D-1 Berlin C5 · TostiaA 1.5 0311Board of directors; Dr. Christian Brulin · K ^ ns-Jütgrn Hamann · Dr Heinz Hannse 'Postan- ^ irilt: CCHERING AG -D-1 Berlin C5 · TostiaA 1.5 0311
Karl Otto Mittolstonscheid · D-. Horst Wuzel Postscheck-Konto: Berlin-West 1175-101. Bankloll/U.l 10310010Karl Otto Mittolstonscheid · D-. Horst Wuzel Postscheck account: Berlin-West 1175-101. Bankloll / U.l 10310010
Stellv.: Dr. Herbert Asmis Borlhor Comm^rzbank AG. Berlin, KoMo-Nr. 108 7iw.c\ [\-»ikloit ..-hl 100 AO■"! CTDeputy: Dr. Herbert Asmis Borlhor Comm ^ rzbank AG. Berlin, KoMo no. 108 7iw. c \ [\ - »ikloit ..- hl 100 AO ■"! CT
Vorsit.-ondfir des Aufsichtsrats Or Eduard v. Grhwaitzkoppon Berliner L)ib-;onto-bank AG, H„: Im, Koiiio-Nr. 2·ί1/:.ί·ο?·. H:i:iklrsil7- '.ι 10Γι AW nc.Chairman of the Supervisory Board Or Eduard v. Grhwaitzkoppon Berliner L) ib-; onto-bank AG, H ": Im, Koiiio-Nr. 2 · ί1 / :. ί · ο? ·. H: i: iklrsil7- '.ι 10Γι AW nc.
Sitz d"r Cc-;r:|l:;clinft: tv.-ilir; und r'.ergkar.nr-n Dorlino: I imiriui-.-Gasclischfift - Γι jn'-iurler D;.rii; - , [Orlin,Seat d "r Cc-; r : | l:; clinft: tv.-ilir; and r'.ergkar.nr-n Dorlino: I imiriui -.- Gasclischfift - Γι jn'-iurler D; .rii; -, [Orlin,
Hari(Ji.-lsrPoislur:AGCIiarlutt>3nb< <rgS<3 HUB 2K υ. AG K?'non HFiD0Q61 Konlo-hi. 11 >S/, Uankloitzahl ΙΜΖΟΪΙΜHari (Ji.-lsrPoislur: AGCIiarlutt> 3nb <<rgS <3 HUB 2K υ. AG K? 'Non HFiD0Q61 Konlo-hi. 11 > S /, Uankloitzahl ΙΜΖΟΪΙΜ
Claims (1)
X ein Saue«stoff- oder Schwefelatom bedeuten... and
X signify an oxygen or sulfur atom.
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19752541855 DE2541855A1 (en) | 1975-09-18 | 1975-09-18 | 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II |
CH857676A CH623571A5 (en) | 1975-09-18 | 1976-07-05 | |
SU762385904A SU795465A3 (en) | 1975-09-18 | 1976-07-28 | Method of preparing 4-(polyalkoxyphenyl)-2-pyrrolidones |
DK408676A DK157919C (en) | 1975-09-18 | 1976-09-10 | ANALOGY PROCEDURE FOR PREPARING HIS UNKNOWN RACEMIC OR OPTICALLY ACTIVE 2-PYRROLIDONE DERIVATIVES |
IL50451A IL50451A (en) | 1975-03-20 | 1976-09-10 | 4-(3,4-dimethoxyphenyl)-2-pyrrolidone-1-carboxylic acid derivatives,their preparation and pharmaceutical compositions containing them |
ES451518A ES451518A2 (en) | 1975-09-18 | 1976-09-14 | 4-(Polyalkoxyphenyl)-2-pyrrolidones (II) |
IE2052/76A IE43723B1 (en) | 1975-09-18 | 1976-09-15 | 4.(alkoxy-phenyl)-2-pyrrolidones |
SE7610275A SE407799B (en) | 1975-09-18 | 1976-09-16 | METHODS OF MANUFACTURING RACEMIC AND OPTICALLY ACTIVE 4- (POLYALCOXYPHENYL) -2-PYRROLIDONES USE AS NEUROPSYCOTROPY DRUGS |
DD194827A DD126894A6 (en) | 1975-09-18 | 1976-09-16 | |
NL7610300A NL7610300A (en) | 1975-09-18 | 1976-09-16 | PROCEDURE FOR PREPARING 4- (POLYALKYL-FE-NYL) -2-PYRROLIDONES AND PROCEDURE FOR PREPARING A MEDICINAL PRODUCT WITH NEURO-PSYCHOTROPIC ACTION. |
JP51111693A JPS5236659A (en) | 1975-09-18 | 1976-09-17 | Racemic and optically active 44*polyalkoxyyphenyl** 22pyrrolidone and neuralgia and mental disease treating agent containing same |
HU76SC578A HU173117B (en) | 1975-09-18 | 1976-09-17 | Process for producing 4-bracket-polyalkoxy-phenyl-bracket closem 2-pyrrolidone derivatives |
CS766054A CS225802B2 (en) | 1975-09-18 | 1976-09-17 | The production of new 4-/polyalkoxyphenoy 1/-2-pyrrolidone |
FR7627961A FR2324299A2 (en) | 1975-09-18 | 1976-09-17 | (POLYALCOXY-PHENYL) -4 PYRROLIDONES-2 AND MEDICINAL PRODUCTS CONTAINING IT |
AT690776A AT349459B (en) | 1975-09-18 | 1976-09-17 | PROCESS FOR MANUFACTURING NEW 2-PYRROL IDONY DERIVATIVES |
CA261,454A CA1077496A (en) | 1975-09-18 | 1976-09-17 | 4-(polyalkoxy-phenyl)-2-pyrrolidone ii |
US05/724,213 US4153713A (en) | 1975-09-18 | 1976-09-17 | 4-(Polyalkoxyphenyl)-2-pyrrolidones (II) |
BE170731A BE846335R (en) | 1975-09-18 | 1976-09-17 | (POLYALCOXY-PHENYL) -4-PYRROLIDINONES-2 AND MEDICINAL PRODUCTS CONTAINING IT |
GB38887/76A GB1563398A (en) | 1975-09-18 | 1976-09-20 | 4-(alkoxyphenyo)-2-pyrrolidones |
CS824554A CS225847B2 (en) | 1975-09-18 | 1982-06-18 | The production of new 4-polyalkoxyphenyl/-2-pyrrolidone |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19752541855 DE2541855A1 (en) | 1975-09-18 | 1975-09-18 | 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II |
Publications (1)
Publication Number | Publication Date |
---|---|
DE2541855A1 true DE2541855A1 (en) | 1977-03-31 |
Family
ID=5956927
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19752541855 Withdrawn DE2541855A1 (en) | 1975-03-20 | 1975-09-18 | 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II |
Country Status (18)
Country | Link |
---|---|
US (1) | US4153713A (en) |
JP (1) | JPS5236659A (en) |
AT (1) | AT349459B (en) |
BE (1) | BE846335R (en) |
CA (1) | CA1077496A (en) |
CH (1) | CH623571A5 (en) |
CS (1) | CS225802B2 (en) |
DD (1) | DD126894A6 (en) |
DE (1) | DE2541855A1 (en) |
DK (1) | DK157919C (en) |
ES (1) | ES451518A2 (en) |
FR (1) | FR2324299A2 (en) |
GB (1) | GB1563398A (en) |
HU (1) | HU173117B (en) |
IE (1) | IE43723B1 (en) |
NL (1) | NL7610300A (en) |
SE (1) | SE407799B (en) |
SU (1) | SU795465A3 (en) |
Cited By (3)
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EP0024030A1 (en) * | 1979-08-09 | 1981-02-18 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrrolidine derivatives, processes for their preparation and pharmaceutical compositions containing them |
EP0358092A1 (en) * | 1988-09-01 | 1990-03-14 | Lonza A.G. | 2-Aza-4-(alkoxycarbonyl)spiro-(4,5)decan-3-one |
WO1992006077A1 (en) * | 1990-10-05 | 1992-04-16 | Schering Aktiengesellschaft Berlin Und Bergkamen | Method of preparing optically active 4-aryl-2-pyrrolidinones |
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US5459145A (en) * | 1988-01-19 | 1995-10-17 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
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JP2578001B2 (en) * | 1989-12-11 | 1997-02-05 | 明治製菓株式会社 | Anti-dementia drug |
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US5514678A (en) * | 1992-03-26 | 1996-05-07 | E. I. Du Pont De Nemours And Company | Arthropodicidal 1,2,4-triazinyl amides |
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US5665754A (en) * | 1993-09-20 | 1997-09-09 | Glaxo Wellcome Inc. | Substituted pyrrolidines |
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GB9326173D0 (en) * | 1993-12-22 | 1994-02-23 | Celltech Ltd | Chemical compounds and process |
US5672622A (en) * | 1994-04-21 | 1997-09-30 | Berlex Laboratories, Inc. | Treatment of multiple sclerosis |
US6060501A (en) * | 1994-06-02 | 2000-05-09 | Schering Aktiengesellschaft | Combined treatment of multiple sclerosis |
US6245774B1 (en) | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
US5786354A (en) * | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
GB9412571D0 (en) * | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
GB9412573D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
GB9412672D0 (en) * | 1994-06-23 | 1994-08-10 | Celltech Ltd | Chemical compounds |
CZ290671B6 (en) * | 1995-02-10 | 2002-09-11 | Schering Aktiengesellschaft | Pharmaceutical preparations intended for inhibition of tumor necrosis factor |
DE19540475A1 (en) * | 1995-10-20 | 1997-04-24 | Schering Ag | Chiral methylphenyloxazolidinones |
GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
GB9526243D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
GB9526246D0 (en) * | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
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GB9608435D0 (en) * | 1996-04-24 | 1996-06-26 | Celltech Therapeutics Ltd | Chemical compounds |
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GB9622363D0 (en) * | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
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GB9713087D0 (en) * | 1997-06-20 | 1997-08-27 | Celltech Therapeutics Ltd | Chemical compounds |
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DE2136571A1 (en) * | 1970-07-24 | 1972-01-27 | UCB SA , Saint Gilles lez Brüssel, (Belgien) | New derivatives of the 2 pyrrohdmon |
DE2413935A1 (en) * | 1974-03-20 | 1975-10-16 | Schering Ag | 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE |
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CA709405A (en) * | 1965-05-11 | Parke, Davis And Company | Methods for producing pyrrolidine compounds | |
US2975193A (en) * | 1959-06-18 | 1961-03-14 | Parke Davis & Co | Organic amine compounds and method of obtaining the same |
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US3644398A (en) * | 1969-04-11 | 1972-02-22 | Robins Co Inc A H | 1-carbamoyl-3-phenylpyrrolidines |
US3956314A (en) * | 1970-07-24 | 1976-05-11 | U.C.B., Societe Anonyme | Derivatives of 2-pyrrolidinone |
JPS5232064B2 (en) * | 1972-06-14 | 1977-08-19 |
-
1975
- 1975-09-18 DE DE19752541855 patent/DE2541855A1/en not_active Withdrawn
-
1976
- 1976-07-05 CH CH857676A patent/CH623571A5/de not_active IP Right Cessation
- 1976-07-28 SU SU762385904A patent/SU795465A3/en active
- 1976-09-10 DK DK408676A patent/DK157919C/en not_active IP Right Cessation
- 1976-09-14 ES ES451518A patent/ES451518A2/en not_active Expired
- 1976-09-15 IE IE2052/76A patent/IE43723B1/en unknown
- 1976-09-16 NL NL7610300A patent/NL7610300A/en not_active Application Discontinuation
- 1976-09-16 DD DD194827A patent/DD126894A6/xx not_active IP Right Cessation
- 1976-09-16 SE SE7610275A patent/SE407799B/en not_active IP Right Cessation
- 1976-09-17 FR FR7627961A patent/FR2324299A2/en active Granted
- 1976-09-17 CS CS766054A patent/CS225802B2/en unknown
- 1976-09-17 US US05/724,213 patent/US4153713A/en not_active Expired - Lifetime
- 1976-09-17 HU HU76SC578A patent/HU173117B/en unknown
- 1976-09-17 AT AT690776A patent/AT349459B/en not_active IP Right Cessation
- 1976-09-17 BE BE170731A patent/BE846335R/en not_active IP Right Cessation
- 1976-09-17 JP JP51111693A patent/JPS5236659A/en active Granted
- 1976-09-17 CA CA261,454A patent/CA1077496A/en not_active Expired
- 1976-09-20 GB GB38887/76A patent/GB1563398A/en not_active Expired
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DE2136571A1 (en) * | 1970-07-24 | 1972-01-27 | UCB SA , Saint Gilles lez Brüssel, (Belgien) | New derivatives of the 2 pyrrohdmon |
DE2413935A1 (en) * | 1974-03-20 | 1975-10-16 | Schering Ag | 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0024030A1 (en) * | 1979-08-09 | 1981-02-18 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyrrolidine derivatives, processes for their preparation and pharmaceutical compositions containing them |
EP0358092A1 (en) * | 1988-09-01 | 1990-03-14 | Lonza A.G. | 2-Aza-4-(alkoxycarbonyl)spiro-(4,5)decan-3-one |
WO1992006077A1 (en) * | 1990-10-05 | 1992-04-16 | Schering Aktiengesellschaft Berlin Und Bergkamen | Method of preparing optically active 4-aryl-2-pyrrolidinones |
US5298628A (en) * | 1990-10-05 | 1994-03-29 | Schering Aktiengesellschaft | Process for the production of optically active 4-aryl-2-pyrrolidinones |
Also Published As
Publication number | Publication date |
---|---|
US4153713A (en) | 1979-05-08 |
NL7610300A (en) | 1977-03-22 |
JPS612660B2 (en) | 1986-01-27 |
AT349459B (en) | 1979-04-10 |
DK157919B (en) | 1990-03-05 |
SU795465A3 (en) | 1981-01-07 |
DK408676A (en) | 1977-03-19 |
ES451518A2 (en) | 1977-10-01 |
HU173117B (en) | 1979-02-28 |
CA1077496A (en) | 1980-05-13 |
DD126894A6 (en) | 1977-08-17 |
CS225802B2 (en) | 1984-02-13 |
FR2324299B2 (en) | 1980-02-01 |
GB1563398A (en) | 1980-03-26 |
SE7610275L (en) | 1977-03-19 |
CH623571A5 (en) | 1981-06-15 |
BE846335R (en) | 1977-03-17 |
SE407799B (en) | 1979-04-23 |
ATA690776A (en) | 1978-09-15 |
IE43723L (en) | 1977-03-18 |
JPS5236659A (en) | 1977-03-22 |
FR2324299A2 (en) | 1977-04-15 |
DK157919C (en) | 1990-08-06 |
IE43723B1 (en) | 1981-05-06 |
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